PROJECT SUMMARY Typhoid and paratyphoid fever are indistinguishable in their symptoms, suggesting that typhoidal Salmonella serovars possess similar virulence strategies. However, the identity of shared virulence strategies that set typhoidal Salmonella serovars apart from non-typhoidal Salmonella serovars, such as S. enterica serovar Typhimurium, remain understudied. Experiments proposed in this application are aimed at addressing this important gap in knowledge. Our long-range goal is to elucidate the molecular mechanisms by which typhoidal Salmonella serotypes manipulate host responses during infection. The objectives of this application are to study the contribution of genome decay in typhoidal Salmonella serovars, which includes gene deletion or disruption (pseudogene formation), to their interaction with the human host. Our central hypothesis is that genome decay in typhoidal Salmonella serovars is a key driver of immune evasion. To test our hypothesis, we will determine whether pseudogen formation enables S. Paratyphi A to evade complement activation (specific aim 1), determine how reduced epithelial invasion caused by genome decay moderates gut inflammation (specific aim 2) and determine how pseudogene formation enhances Peyer's patch colonization (specific aim 3). Our analysis of virulence mechanisms shared among typhoidal Salmonella serovars will be useful, and necessary, to understand how the interplay between pathogen and the innate immune system gives rise to responses that distinguish typhoid/paratyphoid fever from gastroenteritis, thereby ushering in a significant conceptual advance.